ABSTRACT. Soluble oligomers of beta amyloid (A?) protein are the most potent neuroactive structural form of this protein and evidence suggests they cause the synaptotoxic changes resulting in cognitive decline in Alzheimer?s disease (AD) (Selkoe and Hardy 2016, Viola and Klein 2015). A safe and effective drug against A? oligomers should prevent and reverse this synaptotoxicity. CT1812 is the first drug that selectively displaces oligomers from synaptic receptor sites and clears oligomers from the brain into the cerebrospinal fluid (CSF). These first-in-class drugs work by displacing A? oligomers bound to neuronal receptors at synapses. They accomplish this by allosterically modulating a key protein regulator of oligomer receptors (the sigma- 2/PGRMC1 protein complex), thus destabilizing the oligomer binding site and increasing the off-rate of oligomers, which are then cleared into the CSF. As a result, CT1812 restores synapse number and cognitive performance to normal in preclinical AD mouse models (Izzo et al., 2014a, b). This project proposes to evaluate the effect of CT1812 on synapse number and cognitive function in a Phase 1b randomized, double-blind, placebo-controlled clinical trial in AD patients. By combining measurements of cognitive function with novel Positron Emission Tomography (PET) imaging of synaptic density in the same patients, this trial can directly test the mechanism of action of CT1812 and the A? oligomer hypothesis of AD. The PET tracer 11C-UCB-J, which quantitatively images the synaptic protein SV2A, has been used as a measure of synaptic density in humans (Finnema et al., 2016) and can be used as a biomarker of synaptic density loss and regrowth in Alzheimer?s patients. We propose to conduct a clinical trial in 20 A?-positive mild to moderate Alzheimer?s patients (MMSE 18-26) receiving CT1812 or placebo once daily for 3 months, with synaptic density measured via 11C-UCB-J scans and cognitive testing (ADAS-Cog14, ADCS-ADL, CDR-SB) at baseline and 3 months. Our primary aim is to evaluate the correlation between changes in synaptic density and changes in cognitive function. Our secondary aim is to evaluate the correlation between changes in synaptic density and changes in glucose metabolism. We hypothesize that increases in synaptic density as measured with PET will be demonstrated in this cohort, and that these changes will correlate with cognitive improvement. Completion of this pilot study in AD patients will inform the design and methods of the subsequent Phase 2a proof of concept trials with CT1812. Advancement of CT1812 clinical development would substantially improve the lives of the 36 million people worldwide suffering from AD and MCI due to AD, for whom no disease-modifying pharmacological treatments exist.